This invention relates to biodegradable porous reservoir devices for long-term drug delivery, and in particular to biodegradable porous reservoir devices which provide controlled and sustained therapeutic drug levels for extended periods of time.
Currently there are many methods for developing effective delivery devices used in medical applications for delivering drugs or other agents. An ideal pharmaceutical delivery system provides the drug only when and where it is needed and at the appropriate concentration to obtain the designed therapeutic effect. Such methods include biodegradable systems and diffusional delivery systems. Biodegradable systems include a polymer matrix having a therapeutic agent or drug incorporated therein. The biodegradable system releases the drug as the polymer matrix degrades. Usually the polymer matrix contains hydrolytic or enzymatic label bonds on its main molecular chain and as the polymer erodes due to the cleavage of these bonds the encapsulated therapeutic agent is exposed and released. The most often used biodegradable polymers are poly(lactic acid), poly(glycolic acid), poly(ortho ester), and polyanhydrids and their copolymers. The important advantage to using such biodegradable systems is that surgery is not required to remove the waste delivery device after the drug administration period due to the degradation of the polymer matrix. Although biodegradable systems are useful, one disadvantage associated with their use is that the polymers do not deliver the drug at a constant rate and for a long enough period to achieve the required therapeutic effect.
Diffusional delivery systems can be divided into either matrix types or reservoir types. Diffusional delivery systems are based on non-biodegradable polymer materials. The matrix type typically has the therapeutic agent dissolved or mixed with the polymer matrix. The therapeutic agent then diffuses through the polymer matrix. The matrix type system has the advantage that it is easy to make and presents no danger of rupturing or leaking. However, one disadvantage associated with its use is that the drug release may not be constant. The reservoir type is composed of an inner cavity that contains the therapeutic agent which in turn is surrounded by a semipermeable membrane that controls the flow or release of the therapeutic agent. The reservoir type system has the advantage that it provides a zero-order or constant rate of release. However, several disadvantages include the possibility of leaks or ruptures, it is expensive to make, and additional surgery is required to remove the empty carrier.
With respect to ocular structures, currently vitreoretinal diseases are inadequately treated either by repeated topical application of ophthalmic drops or by frequent subconjunctival or intravitreal drug injection. Furthermore, depending on the extent and severity of the ocular disease, systemic drug delivery treatment is occasionally being used. Topical drug-delivery treatment severely limits the access of almost all drugs into intraocular structures. This is due to the heterogeneity of corneal structure being composed of a lipophilic epithelial component (barrier to polar drugs) and a hydrophilic stroma component (barrier to lipophilic drugs). It has been determined that in successful cases less than 8% of the total drug that is being applied topically is able to reach the sites of action in the vitreoretinal structures. On the other hand, the systemic drug-delivery method while effective for transport of lipophilic drugs into vitreoretinal structures is not effective for delivery of hydrophilic drugs from the blood side into the retina and vitreous. The delivery of hydrophilic drugs is severely hindered because of the presence of an impermeable blood-retinal barrier to charged, hydrophilic agents. Furthermore, systemic administration of drugs with narrow therapeutic index often results in a general systemic toxicity. Because of these limitations in delivering the drugs into their sites of action in the vitreoretinal structures, Peyman and coworkers pioneered the method of intravitreal drug administration in the early 1970s in order to achieve therapeutically effective concentration of drugs in the vitreous and retina (Arch. Ophthalmol. 92:42-47, 1974: and Arch. Ophthalmol. 91:416-418, 1974). Unfortunately, the successful treatment of most of the vitreoretinal diseases requires repeated intravitreal drug injection in order to maintain adequate drug concentration in the vitreous for a desired period of time. Even if repeated intravitreal drug administration into an already compromised eye may improve the outcome of certain ocular conditions, the intravitreal strategy suffers from several problems including increased risk of ocular infection, intraocular hemorrhage, and retinal and lens damage. Moreover, the initial drug peak level achieved immediately after an intravitreal bolus injection may result in ocular toxicity, further complicating the disease process. In an attempt to reduce or even eliminate these serious problems while improving the efficacy of ophthalmic agents for treatment of vitreoretinal diseases, several other strategies have subsequently been developed.
One such strategy, which attempts to improve the bioavailability of drugs at the receptor sites in the vitreous and retina, is a drug-delivery system with sustained-release feature. This drug-delivery system includes microspheres (Wood Int. J. Pharmaceutics 7:1-18, 1980). Microspheres of biodegradable polymers have been utilized to prolong the bioavailability of ophthalmic drugs in the retina and vitreous cavity. The use of biodegradable polymers, based on lactic and glycolic acids, in general surgery has clearly demonstrated the biocompatiblility and usefulness of this class of polymers. As such, this information has further encouraged their use as biodegradable carrier in the form of microspheres for controlled drug delivery. Microsphere-incorporated drugs have been shown to prolong the half-life of certain drugs, thus, eliminating the need for repeated intravitreal injection, thereby lowering the risk of complications. In other studies, microspheres have been shown to reduce the toxicity associated with some drugs.
Although kinetic studies indicate that microsphere-drug delivery systems may be useful for sustaining the release of lipophilic drugs, there are inherent problems with these drug delivery techniques regarding their use for intraocular applications. It is also known that microsphere-drug delivery systems have a tendency to diffuse and disperse throughout the vitreous humor when injected into the vitreous. This property causes vitreous haziness and thus, blurred vision occurs for at least 2 to 3 weeks following intravitreal injection. This problem not only complicates the evaluation of the vitreoretinal status in this critical moment of the treatment course, but also precludes the patient to see until the complete resorption of the drug formulation. Nevertheless, the successful formulation of such drug delivery system provides therapeutic drug levels for only 2 to 3 weeks, and when necessary, repeated intravitreal injections are required. Because of these limitations, alternative methods have been pursued.
The need for a well tolerated, biodegradable porous reservoir type drug device for long-term drug delivery is even more pressing in that numerous posterior segment eye diseases would be treated if such a drug device would be available. Such a biodegradable porous drug device would be superior to the existing delivery systems described above because it would not be dispersed throughout the vitreous and it would not require surgical removal following its insertion into the eye. An ideal biodegradable porous drug delivery device should be composed of an inert, biodegradable carrier with one or more pharmacologically active agents, and it should exhibit a slow-release feature for a desired period of time without causing any adverse effects on ocular structures. Such a biodegradable porous drug delivery device will be inserted by physicians into a patient's eye for successful treatment of certain intraocular conditions such as: 1) following vitreoretinal surgeries which predispose the eye to a subsequent development of proliferative vitreoretinopathy (PVR), including long-standing retinal detachments, giant retinal tears, traumatic eye injuries with or without involving foreign bodies, tractional detachments in uveitis, endophethalmitis, or diabetic retinaopathy; 2) complications of immunodeficiency syndrome where viral and other pathogenic organisms affect the retina including CMV retinitis and other viral retinitis; 3) when intraocular pressure is compromised which may consequently cause loss of vision, such as macular edema; 4) inhibition and prevention of neovascularization; and 5) for prevention of cellular proliferation in fistulating glaucoma procedures where removal of vitreous is indicated such as aphakic glaucoma, which does not respond to current therapy. For all these reasons, development of a safe, effective intraocular biodegradable drug device for treatment of posterior segment eye disorders is warranted. Intraocular drug delivery devices with sustained-release feature can have potential clinical applications for effective treatment of posterior segment (vitreoretinal) diseases because most of the vitreoretinal disorders require long-term therapy.
The advantages of such an intraocular biodegradable drug device may include the following: 1) it would eliminate the need for repeated intravitreous drug injection because the device provides drug release for long-term therapy; 2) it would reduce or even abolish drug toxicity associated with the therapeutic levels of antiproliferative and antiviral agents because of its slow-release feature; 3) it would not diffuse or disperse throughout the vitreous cavity, thus, it would not cause vitreous cloudiness; 4) the device can be modified with respect to the rate and duration of drug release, as such, the device satisfies the requirements of a specific therapy, i.e., PVR (2 to 3 months treatment course), CMV retinitis (lifetime treatment), and macular edema (more than 3 months treatment); 5) the device does not require subsequent surgical removal from the eye since it gradually degrades while it is releasing its content; and 6) the drug device can be formed in any desired dimensions and configuration which may be deemed necessary.